J Chem Inf Model - Structure and ligand-based design of mTOR and PI3-kinase inhibitors leading to the clinical candidates VS-5584 (SB2343) and SB2602.

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Resumo

Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical effectors in a commonly deregulated cell signaling pathway in human cancers. The abnormal activation of the PI3K/mTOR pathway has been shown to play a role in initiation, progression, and metastasis of human tumors. Being one of the most frequently activated pathways in cancer, much effort has been directed toward inhibition of the PI3K/mTOR pathway as a novel oncology therapy. Previous work by a number of groups has revealed several selective PI3K and dual mTOR/PI3K inhibitors. However, there are few reports of therapeutic agents with a pan-PI3K/mTOR inhibitory profile within a narrow concentration range. We therefore initiated a drug discovery project with the aim of discovering dual mTOR/PI3K inhibitors which would equipotently inhibit the 4 isoforms of PI3K, a, ?, , and d, and mTOR a compelling profile for powerful blockage of the PI3K/mTOR pathway. A pharmacophore model was generated and used for designing a series of novel compounds, based on a purine scaffold, which potently inhibited mTOR and PI3Ks. These compounds contained a phenol headgroup essential for binding to the target proteins. Early efforts concentrated on finding replacements for the phenol as it was rapidly conjugated resulting in a short half-life in vivo. Compounds with a variety of headgroups were docked into the PI3Ka and mTOR ATP-binding sites, and aminopyrimidine and aminopyrazine were found to make excellent phenol replacements. Further structure guided optimization of side chains in the 8- and 9-positions of the purine resulted in potent inhibitors with good PKDM properties. As the PI3 kinases play a role in insulin signaling, it is believed that targeting mTOR selectively may give the benefit of blocking the AKT-pathway while avoiding the potential side effects associated with PI3K inhibition. As a result we designed a further series of selective mTOR kinase inhibitors. The project was successfully concluded by progressing both a dual mTOR/PI3K inhibitor, SB2343, and a selective mTOR inhibitor, SB2602, into preclinical development. SB2343 has since entered phase 1 clinical development as VS-5584.

Resumo Limpo

phosphoinositid kinas pik mammalian target rapamycin mtor act critic effector common deregul cell signal pathway human cancer abnorm activ pikmtor pathway shown play role initi progress metastasi human tumor one frequent activ pathway cancer much effort direct toward inhibit pikmtor pathway novel oncolog therapi previous work number group reveal sever select pik dual mtorpik inhibitor howev report therapeut agent panpikmtor inhibitori profil within narrow concentr rang therefor initi drug discoveri project aim discov dual mtorpik inhibitor equipot inhibit isoform pik d mtor compel profil power blockag pikmtor pathway pharmacophor model generat use design seri novel compound base purin scaffold potent inhibit mtor pik compound contain phenol headgroup essenti bind target protein earli effort concentr find replac phenol rapid conjug result short halflif vivo compound varieti headgroup dock pika mtor atpbind site aminopyrimidin aminopyrazin found make excel phenol replac structur guid optim side chain posit purin result potent inhibitor good pkdm properti pi kinas play role insulin signal believ target mtor select may give benefit block aktpathway avoid potenti side effect associ pik inhibit result design seri select mtor kinas inhibitor project success conclud progress dual mtorpik inhibitor sb select mtor inhibitor sb preclin develop sb sinc enter phase clinic develop vs

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